Rational discovery of molecular glue degraders via scalable chemical profiling

Mayor‐Ruiz, Cristina; Bauer, Sophie; Brand, Matthias; Kozicka, Zuzanna; Siklos, Marton I.; Imrichová, Hana; Kaltheuner, Ines H.; Hahn, Elisa; Seiler, Kristina; Koren, Anna; Petzold, Georg; Fellner, Michaela; Bock, Christoph; Müller, André C.; Zuber, Johannes; Geyer, Matthias; Thomä, Nicolas H.; Kubicek, Stefan; Winter, Georg E.

doi:10.1038/s41589-020-0594-x

Cited by 227 publications

(239 citation statements)

References 48 publications

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“…While we are preparing our work for publication, two studies identified CDK12 inhibitors that induce CDK12-DDB1 interactions to trigger CCNK degradation (Mayor-Ruiz et al, 2020;Slabicki et al, 2020). Slabicki et al used a correlation of DDB1 mRNA level with drug-sensitivity across hundreds of cancer cell lines as a strategy to discover that the CDK12 inhibitor CR8 recruits CDK12 to DDB1 and leads to the degradation of CCNK.…”

Section: Discussionmentioning

confidence: 99%

Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation

Chen

Cao

et al. 2020

eLife

124

130

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Molecular-glue degraders mediate interactions between target proteins and components of the ubiquitin-proteasome system to cause selective protein degradation. Here, we report a new molecular glue HQ461 discovered by high-throughput screening. Using loss-of-function and gain-of-function genetic screening in human cancer cells followed by biochemical reconstitution, we show that HQ461 acts by promoting an interaction between CDK12 and DDB1-CUL4-RBX1 E3 ubiquitin ligase, leading to polyubiquitination and degradation of CDK12-interacting protein Cyclin K (CCNK). Degradation of CCNK mediated by HQ461 compromised CDK12 function, leading to reduced phosphorylation of a CDK12 substrate, downregulation of DNA damage response genes, and cell death. Structure-activity relationship analysis of HQ461 revealed the importance of a 5-methylthiazol-2-amine pharmacophore and resulted in an HQ461 derivate with improved potency. Our studies reveal a new molecular glue that recruits its target protein directly to DDB1 to bypass the requirement of a substrate-specific receptor, presenting a new strategy for targeted protein degradation.

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Section: Discussionmentioning

confidence: 99%

Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation

Chen

Cao

et al. 2020

eLife

124

130

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“…These studies not only elucidate an important mechanism of these immunomodulatory drugs but also provide evidence that small molecules hold the potential to repurpose E3 ubiquitin ligases for targeting "undruggable" targets, in particular GBM-relevant oncoproteins such as c-Myc, b-catenin or MCL1 (373). Database mining and rational screening have been used successfully to identify molecular glue degraders that specifically target cyclin K, and these approaches will have broad applications for drug discovery (374,375).…”

Section: Therapeutic Targeting Of E3 Ubiquitin Ligasesmentioning

confidence: 99%

Targeting the Ubiquitin System in Glioblastoma

et al. 2020

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Glioblastoma is the most common primary brain tumor in adults with poor overall outcome and 5-year survival of less than 5%. Treatment has not changed much in the last decade or so, with surgical resection and radio/chemotherapy being the main options. Glioblastoma is highly heterogeneous and frequently becomes treatment-resistant due to the ability of glioblastoma cells to adopt stem cell states facilitating tumor recurrence. Therefore, there is an urgent need for novel therapeutic strategies. The ubiquitin system, in particular E3 ubiquitin ligases and deubiquitinating enzymes, have emerged as a promising source of novel drug targets. In addition to conventional small molecule drug discovery approaches aimed at modulating enzyme activity, several new and exciting strategies are also being explored. Among these, PROteolysis TArgeting Chimeras (PROTACs) aim to harness the endogenous protein turnover machinery to direct therapeutically relevant targets, including previously considered “undruggable” ones, for proteasomal degradation. PROTAC and other strategies targeting the ubiquitin proteasome system offer new therapeutic avenues which will expand the drug development toolboxes for glioblastoma. This review will provide a comprehensive overview of E3 ubiquitin ligases and deubiquitinating enzymes in the context of glioblastoma and their involvement in core signaling pathways including EGFR, TGF-β, p53 and stemness-related pathways. Finally, we offer new insights into how these ubiquitin-dependent mechanisms could be exploited therapeutically for glioblastoma.

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“…The fact that the discovery of molecular glues has been so far the result of serendipity has prompted researchers to define rational methods to discover novel molecules acting as glues [123]. Two recent papers have used distinct approaches, bioinformatics and molecular screening, to establish new molecular glue candidates, somehow converging in identifying and characterizing outstanding cyclin K degraders [124,125] (Figure 2).…”

Section: Molecular Glues Allosteric Modulators and Hydrophobic Tagsmentioning

confidence: 99%

“…Oncology: Her2+ and triple-negative breast tumors [111] Covalent protac BTK and BLK CRBN Oncology: chronic lymphocytic leukemia [112] Covalent protac Platform for Halo-tagged proteins. VHL Research use [115] Covalent protac Platform for GFP-tagged proteins VHL Research use [117] Click protac BRD4 and ERK1/2 CRBN Oncology [119] Molecular glue RBM39 E3 ligase receptor DCAF15 Oncology [122] Molecular glue RBM39, cyclinK CRBN Oncology [123] Molecular glue DDB1-CDK12 molecular glue CRBN Oncology [124] Molecular glue CDK12-cyclin K CRBN Oncology [125] Allosteric modulator Aspartate decarboxylase PanD E3-independent Research use, anti-microbial agents [131] Ubiquitin-independent degrader Androgen receptor (AR) (F876L) ND (indirectly, CHIP) Oncology: prostate cancer [137] Ubiquitin-independent degrader Her3 (ErbB3)…”

Section: Concluding Remarks: An Exciting Third Generation Of Protein-mentioning

confidence: 99%

The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents

2020

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The induction of protein degradation in a highly selective and efficient way by means of druggable molecules is known as targeted protein degradation (TPD). TPD emerged in the literature as a revolutionary idea: a heterobifunctional chimera with the capacity of creating an interaction between a protein of interest (POI) and a E3 ubiquitin ligase will induce a process of events in the POI, including ubiquitination, targeting to the proteasome, proteolysis and functional silencing, acting as a sort of degradative knockdown. With this programmed protein degradation, toxic and disease-causing proteins could be depleted from cells with potentially effective low drug doses. The proof-of-principle validation of this hypothesis in many studies has made the TPD strategy become a new attractive paradigm for the development of therapies for the treatment of multiple unmet diseases. Indeed, since the initial protacs (Proteolysis targeting chimeras) were posited in the 2000s, the TPD field has expanded extraordinarily, developing innovative chemistry and exploiting multiple degradation approaches. In this article, we review the breakthroughs and recent novel concepts in this highly active discipline.

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Rational discovery of molecular glue degraders via scalable chemical profiling

Cited by 227 publications

References 48 publications

Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation

Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation

Targeting the Ubiquitin System in Glioblastoma

The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents

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